DESCRIPTION (adapted from applicants abstract): The long term goal of this project is elucidation of the pharmacological basis of decision making, a term which is often referred to in the psychological literature as "executive functions," and the application of the derived knowledge to the treatment and prevention of substance abuse. Both substance abusers and patients with ventromedial prefrontal frontal lobe lesions suffer from impairments in decision-making. Here we plan to study frontal patients and extend the findings to substance abusers. The proposal is guided by a theoretical framework designed to account for the defects in reasoning and decision-making that are so salient in frontal patients. The hypothesis posits that those decision-making defects, specifically those which involve personal and social behavior, are the results of defective activation of somatic markers that normally function as covert or overt signposts for helping with the process of making choices which are advantageous to the organism. In the past few years, we investigated the anatomical, physiological, and cognitive aspects of the neural network presumed to underlie decision-making and somatic marker activation. We found that the failure to enact somatic states results from dysfunction in a neural system in which the ventromedial (VM) prefrontal cortex is one critical region. However, other neural regions, including the amygdala and somatosensory cortices (SI, SII, and insula) are also hypothesized to be components of that same neural system. The operation of this system is thought to be influenced by non-specific neurotransmitter systems through direct or indirect anatomical connections. However, the nature of these neurotransmitter systems, has not been elucidated. Using experimental strategies which we perfected in the study of these patients, here we propose to carry out specific neurotransmitter manipulations and investigate their effects on decision-making in normals and in patients with frontal lobe lesions. In addition, we plan to investigate how another frontal lobe function, namely working memory, is affected by the same manipulations, relative to decision-making. Recent evidence has established that substance abusers suffer from decision-making impairments as revealed by the same laboratory tests which we used to study frontal patients. Ongoing investigations are probing further the link between decision-making, the frontal lobe, and substance abuse. Therefore, the results from this project will help the development of pharmacological therapies that assist in the rehabilitation of 1) substance abusers; and 2) many patients who suffer from disturbances of executive function caused by head injury, stroke, and surgical ablation of tumors.